The present invention relates to the long-term treatment and prophylactic management of intraocular pressure in human patients. Further, the present invention relates to a composition useful for said treatment and management. Further more, the present invention relates to use of a specific compound for manufacturing said pharmaceutical composition. More specifically, the present invention relates to the long term management of hypertension or glaucoma in the eyes of human patients, without causing pigmentation or with causing comparatively minimal pigmentation of the iris, by periodic topical ocular application of a prostaglandin related compound.
Prostaglandins (hereinafter, referred to as PG(s)) are members of a class of organic carboxylic acids, which are contained in tissues or organs of human and most other animals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A): 
On the other hand, some of the synthetic analogues of primary PGs have a modified skeleton. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
Subscript 1: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into xcex1 type (the hydroxyl group is of an xcex1-configuration) and xcex2 type (the hydroxyl group is of a xcex2-configuration).
In addition, some 15-keto (i.e. having an oxo group at position 15 in place of the hydroxy group) prostaglandins and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic reactions during in vivo metabolism of primary PGs. 15-keto PGs have been disclosed in, for example, EP-A-0281239, EP-A-0281480, EP-A-0289349, EP-A-0453127 and EP-A-0690049. These cited references are herein incorporated by reference.
At present, Latanoprost is available commercially in the United States for use as a topical ocular hypotensive and an anti-glaucoma agent. Chemically, Latanoprost is a 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2xcex1 isopropyl ester. One side effect of Latanoprost is a brown pigmentation of the iris found in about 10% or more of the human patients treated with Latanoprost for about three or more months for management of elevated intraocular pressure. Latanoprost possesses a substantial specific binding affinity for the FP receptor. Selen et al have reported that PGF2xcex1-IE, PGE2-IE and latanoprost induced increased iridial pigmentation in cynomolgus monkeys (Survey of Ophthalmology, 41, supplement 2, S125-S128 (1997)). (xe2x80x9cIExe2x80x9d means isopropyl ester.)
Unoprostone isopropyl ophthalmic solution (Rescula(copyright)) has been commercially available outside Europe and the United States for topical application in the treatment of ocular hypertension and glaucoma. Unoprostone isopropyl is a docosanoid, namely 13,14-dihydro-15-keto-20-ethyl PGF2xcex1 isopropyl ester. To the inventor""s best knowledge, Resucla(copyright) has not been commercially used by Caucasians in the management of ocular hypertension or glaucoma by its periodic topical application to the eye at least once a day for a period of at least six months, more than one year prior to the filing date of this application. Preliminary results regarding no iridic pigmentation from a long-term monkey trial with Unoprostone isopropyl have been published. Resucla(copyright) exhibits substantial absence of FP receptor stimulatory activity.
15-keto-latanoprost (13,14-dihydro-15-keto-17-phenyl-18, 19, 20-trinor PGF2xcex1 isopropyl ester) is a promising candidate for use as a topical ocular hypotensive drug. Short-term studies of its use have been reported in U.S. Pat. No. 5,321,128.
The present invention provides methods for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients without causing pigmentation or with causing less pigmentation than latanoprost of the patient""s iris, by periodic topical administration of a prostaglandin related compound.
The present invention also provides a composition suitable for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients by periodic topical ocular administration, which comprises a prostaglandin related compound as an active ingredient.
The present invention also provides use of a prostaglandin related compound for producing a pharmaceutical composition suitable for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients by periodic topical ocular administration.
According to the present invention, the term xe2x80x9cprostaglandin related compoundxe2x80x9d (hereinafter, referred as xe2x80x9cPG related compoundxe2x80x9d) includes any of derivatives or analogs (including substituted derivatives) of a compound having the prostanoic acid basic structure irrespective of the configuration of the 5-membered ring, number of double bonds in the xcex1 or xcfx89-chain, presence or absence of hydroxy and oxo groups or any other substituent, or any other modification.
The nomenclature of the PG related compounds used herein is based on the numbering system of the prostanoic acid skeleton represented in the above formula (A).
The formula (A) shows a basic skeleton of 20 carbon atoms, but the PG related compounds in the present invention are not limited to those having a 20 carbon atom skeleton. In the formula (A), the numbering of the carbon atoms which constitute the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1), and carbon atoms in the xcex1-chain are numbered 2 to 7 towards the five-membered ring, those in the ring are 8 to 12, and those in the xcfx89-chain are 13 to 20. When the number of carbon atoms is decreased in the xcex1-chain, the number is deleted in the order starting from position 2; and when the number of carbon atoms is increased in the xcex1-chain, compounds are named as substitution compounds having respective substituents at position 2 in place of carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the xcfx89-chain, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the xcfx89-chain, the carbon atoms beyond position 20 are named as substituents. Stereochemistry of the compounds is the same as that of the above formula (A) unless otherwise specified.
In general, each of the terms PGD, PGE and PGF represents PG compounds having hydroxy group (s) at positions 9 and/or 11, but in the present specification, these terms also include those PG related compounds having substituents other than the hydroxy group at positions 9 and/or 11 . Such compounds are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogen in place of the hydroxy group is simply named as 9- or 11-dehydroxy compound.
As stated above, the nomenclature of the PG related compounds is based on the prostanoic acid skeleton. However, in case the compound has a similar partial construction as a prostaglandin, the abbreviation of xe2x80x9cPGxe2x80x9d may be used. Thus, a PG compound of which xcex1-chain is extended by two carbon atoms; that is, having 9 carbon atoms in the xcex1-chain, is named as 2-decarboxy-2- (2-carboxyethyl)-PG compound. Similarly, a PG compound having 11 carbon atoms in the xcex1-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG compound, and a PG compound having 10 carbon atoms in the xcfx89-chain is named as 20-ethyl-PG compound. These compounds, however, may also be named according to the IUPAC nomenclatures.
The PG related compounds used in the present invention may include any of PG derivatives or analogs. Accordingly, for example, a PG1 compound having a double bond at 13-14 position and a hydroxy group at 15-position, a PG2 compound having another double bond at 5-6 position, a PG3 compound having further double bond at 17-18 position, a 15-keto-PG compound having an oxo group in place of the hydroxy group at the 15-position, a 15-dehydroxy-PG compound having a hydrogen atom in place of the hydroxy group at the 15-position, or the corresponding 13,14-dihydro-PG compounds wherein in each type of compound the double bond at 13-14 position is single bond, or the corresponding 13,14-didehydro-PG compounds wherein in each type of compound the double bond at the 13-14 position is a triple bond are included. Moreover, examples of substituted compounds and derivatives include a compound wherein the terminal carboxyl group in the xcex1-chain of the above described compound is ester, ether, amide, a pharmaceutically acceptable salt thereof, a compound wherein the number of carbon atoms in the xcex1- or xcfx89-chain is decreased or increased, a compound having side chains (e.g., 1 to 3 carbon atoms) on xcex1- or xcfx89-chains, a compound having substituent(s) such as hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, and oxo, or double bond(s) on the five-membered ring, a compound having substituent(s), such as halogen, oxo, aryl and heterocyclic on the xcex1-chain, a compound having substituents such as halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group and heterocyclic-oxy group on the xcfx89-chain, and a compound having substituent such as lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group and heterocyclic-oxy group at the terminal of the xcfx89-chain of which is shorter, the same as or longer than that of normal prostanoic acid.
In preferred embodiments, the human patients are of the Caucasian race.
In preferred embodiments, the periodic administration is at least once a day for at least six months.
In another preferred embodiment of the invention, the compound administered is a docosanoid.
In yet another preferred embodiment of the invention, the compound administered is Unoprostone isopropyl.
In still another preferred embodiment of the invention, the compound administered is 15-keto-latanoprost.
In another preferred embodiment of the invention, the compound administered is 17-phenyl-18, 19, 20-trinor PGF2xcex1 N-ethylamide 15-keto-17-phenyl-18,19,20-trinor-PGF2xcex1 N-ethylamide or 13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor PGF2xcex1 N-ethylamide.
In still another preferred embodiment of the invention, the compound administered is a 15-keto-16-(3-trifluoro methyl phenoxy)-17,18,19,20-tetranor PGF2xcex1 or a 13, 14-dihydro-15-keto-16-(3-trifluoromethyl phenoxy)-17,18,19,20-tetranor PGF2xcex1, especially their isopropyl esters.
The present invention is directed to the long-term care and management of intraocular pressure and glaucoma in human patients. Latanoprost, 13,14-dihydro-17-phenyl-18,19, 20-trinor PGF2xcex1 isopropyl ester, has been used in such treatment, but causes brown pigmentation of the iris of Caucasians in a significant number of patients (10% or more). Since it is not believed at present possible to predict with relative certainty in which patient iridic pigmentation will occur, this is a significant side effect in a color-conscious world, especially for female patients. The iridic pigmentation usually occurs by three or more months with continuous treatment, i.e., periodic administration on a daily basis. It is believed that the iridic pigmentation results from latanoprost""s high specific binding affinity for the prostaglandin FP or EP receptor. (Journal of Japan Glaucoma Society, 5, 136 (1995))
Now, it has been found that a prostaglandin related compound of the present invention which substantially does not stimulate the prostaglandin FP receptor or possesses an FP specific affinity one-tenth or less than that of latanoprost and is otherwise usable as a topically administered ocular hypotensive, can be safely administered to humans over prolonged time periods without causing dark colored iridic pigmentation. Certain of these compounds are those in which carbon atom number 15 is substituted by an oxo group (15-keto compounds), or those in which carbon atom number 15 is substituted by a hydroxy group and the omega chain beyond carbon atom number 15 contains a straight chain of at least 6 carbon atoms or a straight chain of at least 3 carbon atoms with a ring at the terminal of the omega chain. As above discussed, the compounds of this invention can safely be administered topically for ocular hypotensive effect to human patients over prolonged time periods without causing the brown iridic pigmentation found with Latanoprost.
Prostaglandin related compounds of the present invention and of the following formula (I) are one preferred embodiment. 
wherein W1, W2 and W3 are carbon or oxygen atoms,
L, M and N are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy, hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or a functional derivative thereof;
B is single bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94 Cxe2x89xa1Cxe2x80x94;
R1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, an alkyl group, hydroxy, oxo, aryl or heterocyclic group; and
Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen atom, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group.
A group of particularly preferable compounds among the above described compounds is represented by the general formula (II): 
wherein L, M, R1, A and B are the same definitions described above.
X1 and X2 are hydrogen, lower alkyl, or halogen;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group.
Another preferred embodiment of this invention resides in prostaglandin related compounds of the present invention and of the formula (III): 
wherein W1, W2 and W3 are carbon or oxygen atoms,
L, M and N are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy, hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or a functional derivative thereof;
B is single bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94 Cxe2x89xa1Cxe2x80x94;
R1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, an alkyl group, hydroxy, oxo, aryl or heterocyclic group;
Z is 
wherein R4 and R5 are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R4 and R5 are not hydroxy, lower alkoxy and/or hydroxy (lower) alkyl at the same time; and
Raxe2x80x2 comprises (1) a saturated or unsaturated C3 to C5 straight chain aliphatic hydrocarbon beyond carbon atom number 15 substituted by cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic oxy group at its terminus or (2) a saturated or unsaturated at least C6 straight chain aliphatic hydrocarbon residue beyond carbon atom number 15, which is unsubstituted or substituted with halogen atom, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group.
Still another preferred embodiment of this invention resides in prostaglandin related compounds of the present invention and of the formula (IV): 
wherein W1, W2, and W3 are carbon or oxygen atoms,
L, M and N are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy, hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
Rxe2x80x2 and Rxe2x80x3 is hydrogen atom, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl;
B is single bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
R1 is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, an alkyl group, hydroxy, oxo, aryl or heterocyclic group;
Z is 
wherein R4 and R5 are hydrogen atom, hydroxy, halogen atom, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R4 and R5 are not hydroxy, lower alkoxy and/or hydroxy(lower)alkyl at the same time; and
Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen atom, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower))alkyloxy, aryl, aryloxy, heterocyclic group or hetrocyclic-oxy group; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group.
The compounds used with the present invention can be of the prostaglandins A, B, C, D, E, F, or J type and include subtypes 1, 2, and 3, all as explained in U.S. Pat. No. 5,001,153, the entire content of which is incorporated herein by reference. Compounds usable in the present invention are described in U.S. Pat. No. 5,001,153, and in U.S. Pat. No. 5,312,128, including their ophthalmic preparations.
In the above formula, the term xe2x80x9cunsaturatedxe2x80x9d in the definitions for R1, Ra and Raxe2x80x2 is intended to include at least one or more double bonds and/or triple bonds that are isolatedly, separately or serially present between carbon atoms of the main and/or side chains. According to the usual nomenclature, an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both of the positions.
The term xe2x80x9clower or medium aliphatic hydrocarbonxe2x80x9d refers to a straight or branched chain hydrocarbon group having 1 to 14 carbon atoms (for a side chain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10, especially 1 to 8 carbon atoms for R1 and 1 to 10, especially 1 to 8 carbon atoms for Ra.
The term xe2x80x9chalogen atomxe2x80x9d covers fluorine, chlorine, bromine and iodine. Particularly preferable is a fluorine atom.
The term xe2x80x9clowerxe2x80x9d throughout the specification is intended to include a group having 1 to 6 carbon atoms unless otherwise specified.
The term xe2x80x9clower alkylxe2x80x9d refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
The term xe2x80x9clower alkoxyxe2x80x9d refers to a group of lower alkylxe2x80x94Oxe2x80x94, wherein lower alkyl is as defined above.
The term xe2x80x9chydroxy(lower)alkylxe2x80x9d refers to a lower alkyl as defined above which is substituted with at least one hydroxy group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.
The term xe2x80x9clower alkanoyloxyxe2x80x9d refers to a group represented by the formula RCOxe2x80x94Oxe2x80x94, wherein RCOxe2x80x94 is an acyl group formed by oxidation of a lower alkyl group as defined above, such as acetyl.
The term xe2x80x9ccyclo(lower)alkylxe2x80x9d refers to a cyclic group formed by cyclization of a lower alkyl group as defined above but contains three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d refers to the group of cyclo(lower)alkylxe2x80x94Oxe2x80x94, wherein cyclo(lower)alkyl is as defined above.
The term xe2x80x9carylxe2x80x9d may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups), for example, phenyl, naphthyl, tolyl, and xylyl. Examples of the substituents are halogen atom, lower alkoxy and halo(lower)alkyl, wherein halogen atom and lower alkyl are as defined above.
The term xe2x80x9caryloxyxe2x80x9d refers to a group represented by the formula ArOxe2x80x94, wherein Ar is aryl as defined above.
The term xe2x80x9cheterocyclic groupxe2x80x9d may include mono- to tri-cyclic, preferably monocyclic heterocyclic group which has a 5 to 14, preferably 5 to 10 membered ring having optionally substituted carbon atom(s) and 1 to 4, preferably 1 to 3, of 1 or 2 types of hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, puryl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl, benzimidazolonyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include halogen, and halogen substituted lower alkyl group, wherein halogen atom and lower alkyl group are as described above.
The term xe2x80x9cheterocyclic-oxy groupxe2x80x9d means a group represented by the formula HcOxe2x80x94, wherein Hc is a heterocyclic group as described above.
The term xe2x80x9cfunctional derivative,xe2x80x9d of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.
Suitable xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d include conventionally used non-toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as calcium salt and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like. These salts may be prepared by a conventional process, for example from the corresponding acid and base or by salt interchange.
Examples of the ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower alkynyl ethers such as ethynyl ether and propynyl ether; hydroxy(lower)alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.
Examples of the esters include aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; hydroxy(lower)alkyl ester such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such as methoxymethyl ester and 1-methoxyethyl ester; and optionally substituted aryl esters such as, for example, phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; and aryl(lower)alkyl ester such as benzyl ester, trityl ester and benzhydryl ester.
The amides of A mean a group represented by the formula xe2x80x94CONRxe2x80x2Rxe2x80x3, wherein each of Rxe2x80x2 and Rxe2x80x3 is hydrogen atom, lower alkyl, aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and include for example lower alkyl amides such as methylamide, ethylamide, dimethylamide and diethylamide; arylamides such as anilide and toluidide; and alkyl- or aryl-sulfonylamides such as methylsulfonylamide, ethylsulfonyl-amide and tolylsulfonylamide.
Preferred examples of L and M include hydroxy and oxo, and especially, M and L are hydroxy to provide a 5-membered ring structure of, so called, PGF type.
Preferred A is xe2x80x94COOH, xe2x80x94CH2OH, or its pharmaceutically acceptable salt, ester, ether or amide thereof.
Preferred example of X1 and X2 is that at least one of them is halogen, more preferably, both of them are halogen, especially fluorine, that provides a structure of, so called 16,16-difluoro type.
Preferred R1 is an unsubstituted saturated or unsaturated bivalent lower-medium aliphatic hydrocarbon residue. It may preferably have 1-10 carbon atoms, more preferably, 2-8 carbon atoms.
Examples of R1 include, for example, the following groups:
xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1C xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1C xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2 xe2x80x94CH2 xe2x80x94CH (CH3) xe2x80x94CH2xe2x80x94
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x89xa1CH xe2x80x94CH2 xe2x80x94CH2 xe2x80x94CH2 xe2x80x94CH2 xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2(CH3)xe2x80x94CH2xe2x80x94,
Preferred R2 is a single bond or a saturated or unsaturated bivalent lower to medium aliphatic hydrocarbon residue, which may preferably have 1-10 carbon atoms, more preferably 1-8 carbon atoms, especially 1-6 alkylene.
Preferred R3 is a hydrogen atom, aryl or aryloxy.
Preferred Ra is a hydrocarbon containing 1-10 carbon atoms, more preferably, 1-8 carbon atoms and, especially, that having 7 carbon atoms beyond carbon atom number 15.
Preferred Raxe2x80x2 is a straight chain beyond carbon atom number 15 of at least 6 carbon atoms, or at least 3 carbon atoms with a ring, more preferably a phenyl ring, at the terminal of the omega chain.
Preferred Rxe2x80x2 and Rxe2x80x3 is hydrogen atom or C1-6 alkyl, C2-6 alkenyl and C3-6 alkynyl.
The configuration of the ring and the xcex1- and/or xcfx89 chains in the present invention may be the same as or different from that of the primary PGs. However, the present invention also includes a mixture of a compound having a primary type configuration and a compound of a non-primary type configuration.
When a 15-keto-PG compound of the present invention has for example a single bond between carbon atom number 13 and 14, the compound may be in the keto-hemiacetal equilibrium by formation of a hemiacetal between hydroxy at position 11 and oxo at position 15.
If such tautomeric isomers as above are present, the proportion of both tautomeric isomers varies with the structure of the rest of the molecule or the kind of the substituent present. Sometimes one isomer may predominantly be present in comparison with the other. However, it is to be appreciated that the compounds used in the invention include both isomers. Further, while the compounds used in the invention may be represented by a structure formula or name based on keto-type regardless of the presence or absence of the isomers, it is to be noted that such structure or name does not intend to exclude the hemiacetal type compound.
The present invention includes any of the isomers such as the individual tautomeric isomers, a mixture thereof, or the optical isomers, a mixture thereof, a racemic mixture, and other steric isomers useful for the same purpose.
Compounds useful in the practice of this invention are 13,14-dihydro-15-keto-20-ethyl PGF2xcex1 isopropyl ester; 13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF2xcex1 isopropyl ester; 17-phenyl-18,19,20-trinor-PGF2xcex1N-ethylamide; 15-keto-17-phenyl-18,19,20-trinor PGF2xcex1 N-ethylamide; 13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor PGF2xcex1 N-ethylamide; 15-keto-16-(3-trifluoromethyl phenoxy)-17,18,19,20-tetranor PGF2xcex1 isopropyl ester and 13,14-dihydro-15-keto-(3-trifluoromethyl phenoxy)-17,18,19,20-tetranor PGF2xcex1 isopropyl ester.
In the method of the present invention, the above-described compounds are topically administered to the affected eye once or twice a day for at least six months, up to a time period as long as required, to complete treatment for elevated ocular pressure or glaucoma, as needed, or to maintain a prophylactic level for six months or longer, without causing iridic pigmentation, especially the brown pigmentation caused by long term use of Latanoprost.
The pharmaceutical composition of the present invention include ophthalmic solution and ointment. The ophthalmic solution may be prepared by dissolving the active ingredient into sterilized aqueous solution such as saline or buffer. A powder composition for ophthalmic solution to be dissolved before use may also be used. The ophthalmic ointment may be prepared by mixing the active ingredient with ointment base.
The pharmaceutical composition of the present invention will usually have a concentration of less than approximately 0.20% (w/v) of active compound. Preferred concentrations are usually within the concentration range of about 0.00005 to 0.18% (w/v).
The composition of the present invention may further be admixed with any of pharmaceutically active agents in so far as said agent is compatible with the purpose of the present invention.